Candiduria is a common nosocomial infection afflicting the urinary tract. This review is aimed at providing an updated summary of the problem in hospitalized adult patients. A review of English Medline literature published between Jan 1970 until June 2007 was performed. Reviews, clinical trials and case-controlled studies in adult patients were included. Risk factors for candiduria included urinary indwelling catheters, use of antibiotics, elderly age, underlying genitourinary tract abnormality, previous surgery and presence of diabetes mellitus. Presence of candiduria may represent only colonization and there are no consistent diagnostic criteria to define significant infection. Candiduria may not be associated with candidemia and most cases are asymptomatic. Asymptomatic candiduria is usually benign, and does not require local or systemic antifungal therapy. Physicians need to confirm the infection by a second sterile urine sample, adopt non-pharmacologic interventions and modify risk factors. Mortality rate can be high particularly in debilitated patients and awareness to validate candiduria is necessary to stratify treatment according to patient status. Appropriate use of anti fungal drugs, when indicated, should not replace correction of the underlying risk factors. Treatment of symptomatic candiduria is less controversial and easier.

Candida urinary tract infections are an in­creasingly prevalent nosocomial problem with uncertain significance.[1] The presence of Candida species (Spp) in urine samples presents the physician with a challenge as to whether the candiduria represents colo­nization or, lower or upper urinary tract infection including ascending pyelonephritis and renal candidiasis with sepsis.[2],[3],[4],[5] Manage­ment has been inconsistent because of lack of information about the natural history of candiduria, which has not been studied properly.[6],[7],[8],[9],[10],[11] The aim of this review is to give an update on the problem in hospi­talized adult patients and try to answer the three challenging classical questions in managing candiduria which are: whom to treat?, when to treat? and, for how long to treat?

A review of English Medline literature published between 1970 and June 2007 was performed, including the guidelines for treatment of candidiasis by the Infectious Diseases Society of America (IDSA). Arti­cles related to selected populations such as critically ill patients, pediatric age-group, neonates, renal transplant recipients, and studies on candidemia were excluded.

Epidemiology

Candiduria is rarely seen as a community acquired infection in a structurally normal urinary tract, and in healthy people.[3],[6],[12] It is increasingly becoming an important sub­group of nosocomial urinary tract infec­tions (10-15%) and almost all are caused by Candida spp.[3],[10],[11],[13] The prevalence of candiduria varies in the hospital setting and is most prevalent among patients in intensive care units (ICU), more specifi­cally surgical ICU and in leukemia and bone marrow transplant units.[2][,5],[14],[15]

Risk Factors

A review of the epidemiology of candi­duria including all retrospective reviews, case-controlled studies and a large pros­pective surveillance study on candiduria, showed that the common risk factors include urinary tract instrumentation, prior surgical procedures, recent use of antibio­tics, advanced age, female sex, diabetes mellitus, immunosuppressive therapy and prolonged hospital stay.[2],[3],[5],[6],[10],[16],[17],[18] In a recent case-controlled study, it was shown that that the risk to develop candiduria was increased by 12-fold after urinary catheter­rization, six-fold each after the use of broad spectrum antibiotics and urinary tract abnormalities, four-fold following abdominal surgeries, two-fold in the presence of dia­betes mellitus, and one-fold in association with corticosteroid administration.[1] However, no significant difference was found between the compared groups in terms of female sex, and age.

Candida was the causative pathogen in 27% of all urinary tract infections related to indwelling catheters.[19] Use of Foley's catheters was associated with candiduria in 78% of the patients although a variety of other devices such as suprapubic catheters and nephrostomy tubes were also noted. These catheters serve as a portal of entry for microorganisms into the urinary system where they colonize if left in place long enough.[3],[10]

Use of antibiotics was a major risk factor to develop Candida urinary tract infection; it is likely to contribute to colonization by Candida spp by suppressing endogenous bacterial flora, primarily in the gut and lower genital tract and possibly in the superficial area adjacent to the urethral meatus. It may interfere with phagocyte function and anti­body formation with subsequent impaired host defense mechanisms against Candida infection.[1],[3],[11]

Previous surgery was a factor associated with candiduria and more than half of the patients who had a surgical procedure per­formed within the preceding month developed candiduria.[10] Whether surgery per se, or the need for a urinary drainage devices in the peri-operative period was the most important factor, could not be determined.

In a large multicenter study of candiduria in hospitalized patients, only 11% had no underlying illness recorded, 90% of patients had received antibiotics in the month pre­ceding documentation of candiduria and 83% had urinary drainage devices in place. Other predisposing factors were present in most patients including surgical procedures, diabetes mellitus, urinary tract abnormal­lities such as neurogenic bladder and obs­truction, and malignancy. Diabetes mellitus was the most common underlying disease seen in 39% of the patients.[10] It was the most common underlying disease noted in almost every study of candiduria.[1],[3],[20] It was proposed that diabetes predisposes to Candida colonization of the vulvo-vesti­bular area in women by enhancing urinary fungal growth in the presence of glyco­suria, by lowering host resistance to invasion by Candida spp. as a consequence of impaired phagocyte activity, and pro­moting stasis of urine in a neurogenic bladder with more likelihood to undergo urinary tract instrumentation and to receive antibiotics.[3],[10] However, the exact mechanism to for its contribution to candiduria is still not clear.[1] Clinical presentation in dia­betic patients with candiduria range from lower urinary tract colonization to asympto­matic infection, cystitis, emphysematous cys­titis, pyelonephritis and perinephric abscess.[20] Interestingly, men and women were equally represented among the diabetic popula­tion.[10] However, in large surveys in terms of gender difference in candiduria, women outnumbered men.[6],[10]

Microbiology

Most observational studies of candiduria have reported Candida albicans (C. albicans) as the predominant causative organism seen in more than 51 % cases, followed by C. glabrata (16 %) and C. tropicalis.[1],[6],[10] The candida species varies depending on the site of infection. Non-albicans Candida spp are common and more prevalent than C. albicans in sites such as oropharynx and vagina.[3],[4],[6],[10],[11],[15] It has been suggested that Candida spp causing candiduria might also be shifting to non-albicans Candida, the most prevalent of which was C. tropicalis (43%). These differences in the microbiological pat­tern of candiduria remain unexplained currently[21],[22][Table - 1]. Mixed isolates were found in 10% of patients with nosocomial candiduria.[6]

Strain persistence was exceedingly fre­quent in candiduria and was documented in both persistent and recurrent infections. Therefore, species identification is not use­ful in differentiating persistent from recurrent infections. However, molecular methods would certainly be useful in this regard.[23]

Pathogenesis

The significance of systemic factors in the defense against urinary candida infection is unknown, but secretions from the prostate gland in men and from periurethral gland in women have been reported to be fungis­tatic. In addition, other normal flora may suppress growth of Candida at sites on mucous membranes. Lower urinary tract candidiasis is usually the result of a retro­grade infection, while renal parenchymal infection often follows candidemia.[3],[24]

Ascending Infection

Although it is the most common route for bacterial infection of the urinary tract, the pathogenesis of ascending infection with Candida spp is not clearly known.[2] Cathe­terization can cause infection by introducing organisms during the catheterization process or by allowing migration of the organisms into the bladder along the surface of the catheter from the external peri-urethral sur­faces. Ascending infection that originates in the bladder can lead to upper urinary tract infection, especially if vesicoureteric reflux or obstruction of urinary flow occurs.

Hematogenous Infection

Recently, experimental studies have indi­cated that multiple micro-abscesses develop through out the renal cortex following which the yeast penetrates through the glomeruli into the proximal tubules and are then shed into the urine. Hematogenous spread of Candida spp to the kidney was the most com­mon route in renal candidiasis and was well verified in majority of patients with dissemi­nated candidiasis who had renal involvement at autopsy.[2],[3],[25],[26]

Diagnosis

The presence of Candida spp in urine, on examination or culture, does not necessa­rily imply clinical significance. The deter­mination of the significance of candiduria can be blurred and difficult. Unfortunately, clinical criteria are insufficient to distin­guish reliably among the clinical types. The finding of Candida spp in the urine could mean that the patient has cystitis or pyelo­nephritis or most likely it may reflect only colonization of the perineum, indwelling urinary catheter or the bladder. Currently, neither sensitive nor specific laboratory diag­nostic tests are available to reliably distin­guish infection from colonization.

Contamination

Contamination is common, especially if the specimen is suboptimal urine collection from a catheterized patient or a woman who has heavy Candida colonization of the perineum. A small amount of the organisms that may find their way into the collected urine sample can grow and may multiply quickly. Usually, a second sterile urine sample should be clear.[2],[3]

Colonization

Colonization is usually asymptomatic adhe­rence and settlement of the Candida spp on the drainage catheters or foreign bodies in the urinary tract and, may result in high concentration of Candida colonies in urine cultures. Confirmation of candiduria by a second sterile urine examination after chan­ging the catheter or a clean catch or supra­pubic sample is required, before further investigations and initiation of treatment.[2],[3]

Asymptomatic candiduria

Most patients with candiduria are asymp­tomatic and there are no associated signs or symptoms.[3] Quantitative cultures with colony counts of > 100,000 cfu/ml of urine are associated with infection in patients with­out indwelling urinary catheters. In contrast, clinically significant renal candidiasis has been reported even with low colony counts of 1000 cfu/ml of urine.[2]

Pyuria usually supports the diagnosis of infection.[3],[20] However, it may be a result of coexistent bacteriuria or mechanical injury of the bladder mucosa caused by the presence of an indwelling catheter. Absence of pyuria and low colony counts tend to role out Candida infection. The low speci­ficity of pyuria as well as low colony counts of 1000 cfu/ml of urine, requires careful interpretation and proper clinical correla­tion. Quantitative Candida test in urine has little value in localizing the anatomic site of the infection. Rarely, finding a granular cast containing Candida hyphal elements localizes the infection to renal parenchyma with low sensitivity but high specificity.[3],[27]

Candida cystitis

Candida Cystitis is symptomatic lower uri­nary tract infection and presents with symp­toms and signs of bladder irritation including dysuria, hematuria, frequency, urgency and suprapubic tenderness. A symptomatic pa­tient with local invasive fungal infection of the bladder rarely requires cystoscopy unless obstruction or presence of a fungus ball is suspected.

Candida pyelonephritis

Candida pyelonephritis can be associated with candidemia, sepsis and/or septic shock. It is uncommon and seen in hospitalized patients with diabetes and renal insufficiency with papillary necrosis and obstructive uro­pathy. It is indistinguishable from bacterial pyelonephritis and urosepsis. Often, it is com­plicated by suppurative disease, resulting in pyonephrosis and focal abscess formation. Fungus ball is a major complication, and consists of yeast, hyphal elements, epithelial and inflammatory cells and sometimes, renal medullary tissue secondary to papillary nec­rosis. It may complicate ascending or des­cending infections; especially in the pre­sence of obstruction and stasis.

Candiduria and fever may be the only clues and the first indications of systemic inva­sive candidiasis in high-risk patients. They include patients with neutropenia and renal, liver or bone marrow transplant recipients as well as those who have undergone inva­sive urologic procedures. For patients with candiduria who have fever and/or sepsis, it is necessary to obtain blood cultures and per­form radiological investigations to determine the anatomic source of candiduria.[3],[28]

Management

Candiduria does not cause candidemia in most of the patients unless urinary tract obstruction is present.[29] An understanding of the anatomic site of infection along with patient's condition (elderly, catheterized) would determine the nature of treatment. There is a lot of controversy about whether, and when to treat, the most appropriate anti fungal agents to be used, as well as systemic versus local bladder irrigation.[3],[5],[6],[10]

Strategies for management are based on presence or absence of genitourinary tract abnormalities, risks for systemic infection or invasive candidiasis and the potential to develop complications from infection. As an initial intervention, removal of an indwelling catheter is recommended.[20] Current available evidence shows that the discontinua­tion of catheter use alone might result in eradication of candiduria in almost 40% of asymptomatic patients. After a new catheter was inserted, untreated candiduria resolved in 20% of patients.[3],[5],[6] Systemic therapy demonstrated that clinical benefits were less apparent in elderly, debilitated or minimally symptomatic patients without catheter re­moval, and were unable to document con­tinued eradication of the Candida in the urine two weeks after the discontinuation of the anti fungal therapy. Not surprisingly, candiduria was more common at two weeks follow-up visit in those patients whose catheters remained in place.[6] Persistent can­diduria, despite treatment, may warrant ultra­sonography or CT scan of the kidney.[3],[5]

Based on evidence from clinical expe­rience, descriptive studies and other reports, asymptomatic candiduria is usually benign and self-limiting, if the predisposing factors are corrected. Although properly designed randomized controlled studies are lacking, available data indicates that routine treat­ment is not indicated. However, treatment is indicated in patients at high-risk for invasive candidiasis.[30] Nevertheless, asymptomatic candiduria may be considered as a marker of high morbidity/mortality in elderly and debilitated patients with underlying diseases including diabetes mellitus.[6],[10],[31]

If treatment is considered in symptomatic patients, fluconazole is the anti fungal drug of choice provided the organism isolated is not C. glabrata or C. krusei. Treatment with fluconazole, 200 mg/day, for 7-14 days or with intravenous amphotericin B deoxy­cholate at doses of 0.3-1.0 mg/kg/day for 1-7 days has been successful based on moderate evidence from a randomized clini­cal trial. Short courses of therapy are not re­commended; therapy for 7-14 days is more likely to be successful.[5],[6] In a randomized controlled trial of 22 patients, candiduria persisted in 68% patients who received no anti fungal therapy versus 39% among indivi­duals who received fluconazole therapy.[18]

Fluconazole is potentially useful because of the high concentrations of active drug in the urine, is better tolerated and is less likely to be associated with the emergence of resistance during therapy. It is advocated as a safe and effective alternative to ampho­tericin B for the treatment of serious Can­dida infections in organ transplant recipients, especially those receiving cyclosporine.[32] Treatment of Candida can be guided by in vitro susceptibility testing. Individual isolates do not necessarily follow the general pattern. For example, C. albicans is usually suscep­tible to all major agents. However, azole resistance for this species is well described especially among HIV-positive patients.[5],[33] The greatest concern for fluconazole resis­tance is related to C. glabrata and C. krusei isolates which require maximal doses of amphotericin B. Amphotericin B resistance appears uncommonly among isolates of C. tropicalis and C. parapilosis.[5]

Nevertheless, susceptibility testing of Can­dida is not considered a routine procedure in many laboratories, it is not always avai­lable and is not universally considered as the standard of care. The new anti fungal drug voriconazole can be used, especially in severe sepsis or septic shock but its use is determined by the renal function.[34] Echi­nocandin anti fungal agents (caspofungin, micafungin, and anidulafungin) can be used although low sub-therapeutic levels are achieved in the urine because the drug has poor glomerular filtration with subsequent diminished tubular secretion.[35],[36]

The alternative choice for C. glabarata is flucytocine with excellent activity against non-albicans candida. The drug achieves high concentrations in the urine of patients who do not have renal failure. Its limitations included bone marrow, hepatic and gastro­intestinal toxicity and de novo resistance which is seen in 25% of C. albicans strains, particularly when used as monotherapy.[3],[5],[37]

There are few case series and prospective studies that have compared the various the­rapeutic agents. Oral fluconazole has a more delayed but more lasting effect on candi­duria than amphotericin B bladder irrigation. Patients receiving amphotericin B bladder irrigation had higher rates of eradication two days after the beginning of therapy than those receiving oral fluconazole but the cure rates were similar one month after the be­ginning of the therapy. Although amphote­ricin B bladder irrigation has been highly effective in the eradication of Candida cystitis, it is inconvenient to insert a cathe­ter in non-catheterized patient and a 5-day course of localized bladder therapy is in­convenient. Such therapy may be necessary in patients with renal insufficiency.[3],[16],[20],[38],[39]

Continuous amphotericin B bladder irriga­tion was superior to intermittent treatment in terms of efficacy, ease of administration and patient comfort.[40] Recurrence was more common with amphotericin B bladder irrigation compared to fluconazole therapy.[38],[41] The rate of eradication seven days after therapy was higher in patients who received oral fluconazole for four days or single dose of intravenous amphotericin B than in those who underwent bladder irrigation with am­photericin B for three days.[41] A single intravenous injection of amphotericin B causes persistent and sustained urinary ex­cretion of the drug in levels that inhibit Candida spp. and thereby may permit suc­cessful single or pauci dose therapy of can­diduria in some patients with a minimum toxicity.[42],[43]

In patients with Candida pyelonephritis, systemic therapy together with adequate drainage of the upper urinary tract is essen­tial. Treatment with systemic antifungal agent (oral or intravenous) is indicated to eradi­cate the infection. Long-term antifungal the­rapy and drainage is needed after relieving the obstruction and identifying local compli­cations by prompt imaging. Systemic anti fungal therapy used for treatment of sys­temic candidiasis is with either parenteral amphotericin B >0.6 mg/kg/day or fluco­nazole 6 mg/kg/day.[5]

No data is available regarding the efficacy of the less nephrotoxic lipid formulations of amphotericin B in treatment of patients with ascending Candida pyelonephritis or renal candidiasis. Given the favorable ratio of therapeutic effectiveness of fluconazole to toxicity, maintaining conventional doses of the drug in presence of renal insuffi­ciency may achieve therapeutic concentra­tions in the urine necessary for eradicating non-albicans Candida.[5],[44]

Removal of the nephrostomy tube or a replacement by a new one as well as sur­gical removal of the obstructing fungus ball is the most important part of the manage­ment. The nephrostomy tube also serves as a route for local administration of high do­ses of amphotericin B or fluconazole, when renal insufficiency exists with the resultant decreased therapeutic urine concentrations of the drug.

Renal candidiasis is usually due to hemato­genous seeding to the kidneys, and asso­ciated with candidemia, which may present with sepsis, hemodynamic instability and re­nal insuffeciency. Treatment should be with high dose systemic amphotericin B (0.6 mg/ kg/day) or parenteral fluconazole (6 mg/kg/ day). The optimal duration of therapy has not been determined.[3],[5],[45] Candidemia is rarely the consequence of candiduria and usually occurs in the presence of upper urinary tract obstruction.[29],[46]

Conclusion

Nosocomial urinary tract infection resulting in candiduria more common in patients with indwelling urinary catheters, systemic anti­biotic use, underlying genitourinary abnor­mality, previous surgery and diabetes mel­litus. Most cases are asymptomatic and re­quire no treatment. Progression to candied­mia is rare unless patients are at high-risk for invasive disease. Mortality with candi­duria can be high in debilitated patients and those in advanced age. If treatment is indicated, the drug of choice is fluconazole. Identification of Candida spp may be nece­ssary in complicated cases to decide on the anti fungal drug of choice and response to therapy.

The approach to patients with candiduria needs to be individualized and the two important determinants of decision to treat include the extent of genitourinary tract involvement and renal function. Physicians are urged to have an early validation of candiduria considering the status of the pa­tient by stratifying their risks[47][Figure - 1].

Recommendations

Large-scale surveys of candiduria are needed in certain populations at risk to find the true incidence of the disease and com­pare the microbiology patterns, which will help in further understanding of the problem in our population.

Acknowledgement

For Hail Al-abdely who supported to com­pose the review and for Carol A. Kauffman from University of Mitchigan and Peter G pappas from University of Alabama for their permission .